Because of the promising clinical activity of certain taxanes (e.g., paclitaxel) against various types of cancer, there is an ongoing need for different methods for preparing paclitaxel and other taxane molecules, including paclitaxel derivatives and analogues. It is believed that the preparation of paclitaxel derivatives and analogues may result in the synthesis of compounds with comparable or greater potency, superior bioavailability, and/or fewer side effects than paclitaxel. Interconversion of one taxane molecule into another taxane molecule is one route to provide various paclitaxel derivatives and analogues for further study of their biological properties.
Murray et al. describe a process for converting taxol A, taxol B, and taxol C to taxol A or docetaxel (U.S. Pat. Nos. 5,679,807 and 5,808,113). The process generally includes reductive deoxygenation of the C-3′ amide group of a fully protected taxane molecule using Schwartz's reagent to form an imine, followed by hydrolysis of the imine to a primary amine. Subsequent acylation of the primary amine with benzoyl chloride or tert-butyloxycarbonyl anhydride can produce taxol A or docetaxel, respectively.
In another example, Kingston et al. describe the conversion of cephalomannine into paclitaxel by substituting the 2-methyl-2-butenoyl group on the C-13 side chain of cephalomannine with a benzoyl group (U.S. Pat. No. 5,319,112). The methodology generally includes in sequential order: hydrogenation of the 2-methyl-2-butenoyl group, benzoylation of the C-2′ hydroxyl group, protection of the C-7 hydroxyl group as its trichloroethyloxycarbonyl group, reaction of the C-3′ amide functionality with oxalyl chloride followed by addition of water, reaction with diphenylcarbodiimide to create a free amine at the C-3′ position followed by acyl migration of the benzoyl group from the C-2′ hydroxyl group, and removal of the trichloroethyloxycarbonyl group.
However, there is still a need for more efficient and higher yielding synthetic methodologies for converting taxane molecules into other taxane molecules, which may be more potent anti-cancer compounds.